The long-term goal of the proposed research is to better understand the pathophysiology of irritable bowel syndrome (IBS), in the hope to develop more effective treatments. Despite the high prevalence and high human and economic costs of IBS, the disorder is poorly understood, and existing treatment options remain unsatisfactory. IBS is a disorder of altered brain-gut interactions, characterized by enhanced stresssensitivity and greater prevalence in women. Both peripheral and central abormalities have been demonstrated. Centrally, it is characterized by enhanced perception of gut stimuli (resulting in abdominal pain and discomfort), associated with altered neural responses regulating intestinal motility and secretion (resulting in altered bowel habits). The current proposal uses cutting edge brain imaging, genetic and mathematical techniques to characterize distinct brain networks (intermediate brain phenotypes) concerned with the processing of visceral afferent information, with the modulation of visceral pain perception, and with determining arousal and stress sensitivity, and possible associations of these intermediate phenotypes with polymorphisms in several candidate genes. This goal will be accomplished by studying 300 Caucasian subjects (200 IBS patients, 100 healthy controls, 50% women) in 3 Specific Aims: In Aim A, by using fMRI combined with advanced analysis techniques, we will characterize alterations in the activity and connectivity of distinct brain networks concerned with pain processing, pain modulation, and arousal/emotional regulation in patients and controls. We will look for possible associations between functional network responses and selected candidate gene polymorphisms, for gene-gene, gene-early life event, and gene-sex interactions in shaping network responses. In Aim B, we will analyze all brain structural MRI images from Aim A using voxel-based morphometry for structural differences between IBS patients and controls, and search for possible associations of such regional brain volume changes and candidate genes. In Aim C, we will study perceptual and autonomic responses to somatic pain stimuli, and correlate these (as well as visceral pain responses obtained in Aim A) with intermediate brain phenotypes, as well as with genetic polymorphisms. A better understanding of brain circuits which underlie predominant symptoms, and associated genetic traits will greatly facilitate the development of better treatments for these common Gl disorders.